Styrene metabolism

Cox HHJ, BW Faber, VNM van Heiningen, H Radhoe, HI Doddema, W Harder (1996) Styrene metabolism in Exophilia jeanselmei and involvement of a cytochrome P-450-dependent styrene monooxygenase. Appl Environ Microbiol 62 1471-1474. 

By means of an apparent Michaelis constant (A mapp) together with a maximum rate ( max) of butadiene metabolism both obtained with human liver microsomes (Filser et al., 1992), Filser et al. (1993) constructed a human model which was later extended by Csanady et al. (1996) for the butadiene metabolites epoxybutene and diepoxybutane. For butadiene and epoxybutane, the required human tissue air partition coefficients were measured using autopsy material (Table 23). Filser et al. (1993) investigated the influence of styrene co-exposure on butadiene metabolism by assuming competitive interaction. Simulations for a 70-kg man exposed over 8 h to 5 or 15 ppm [11 or 33 mg/m3] butadiene indicated total amounts of butadiene metabolized of 0.095 and 0.285 mmol, respectively, reduced by about 19% and 37% as a result of co-exposure to 20 and 50 ppm styrene, respectively. No influence of butadiene on styrene metabolism was noted. 

Tomero-Velez, R. and Rappaport, S.M., Physiological modeling of the relative contributions of styrene-7,8-oxide derived from direct inhalation and from styrene metabolism to the systemic dose in humans, Toxicol. Sci., 64, 151-161, 2001. 

Nakajima T, Elovaara E, Gonzalez FJ, Gelboin HV, Raunio H, et al. 1994. Styrene metabolism by cDNA-expres-sed human hepatic and pulmonary cytochromes P450. Chem. Res. Toxicol. 7 891-96... 

As discussed in Section 13.3 concurrent exposure to noise and some organic solvents and solvent mixtures is ototoxic. Styrene is an example of an ototoxic compound, with exposures to it causing permanent hearing threshold shifts and outer hair cell damage. Ethanol alone does not affect auditory sensitivity, yet, when combined with styrene it induces hearing and outer hair cell losses in test animals in levels greater than those caused by styrene alone. The potentiation of the ototoxicity of styrene by ethanol is ascribed to the altering of styrene metabolism by ethanol. 15 ... 

Ihe first study focusing on styrene metabolism concerned a Pseudomonas fluorescens strain [15]. During growth of this strain, under a styrene... 

Figure 4. Formation of 2-phenylethanol as a side product in styrene metabolism.

Niessen, W.M. Liquid chromatography/electrospray tandem mass spectrometry characterization of styrene metabolism in man and in rat. Rapid Commun. Mass Spectrom. 

Reports of organ toxicity upon chronic exposure to styrene are rare however, since the main intermediate in styrene metabolism is an epoxide (styrene-7,8-oxide), hepatotoxicity due to covalent binding at the site of formation appears to be a possibility. Both of these substances, styrene (a Group 3 agent) and its oxide (recently upgraded to a Group 2A as probably carcinogenic to humans) have been shown to produce chromosomal aberrations under certain conditions. 

Toda, H. and Itoh, N. (2012) Isolation and characterization of styrene metabolism genes from styrene-assimilating soil bacteria Rhodococcus sp. ST-5 and ST-10. 

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

Hartmans S, JP Smits, MJ van der Werf, F Volkering, JAM de Bont (1989) Metabolism of styrene oxide and 2-phenylethanol in the styrene-degrading Xanthobacter strain 124X. Appl Environ Microbiol 55 2850-2855. 

Warhurst AM, KF Clarke, RA Hill, RA Holt, CA Fewson (1994) Metabolism of styrene by Rhodococcus rhodochrous NCIMB 13259. Appl Environ Microbiol 60 1137-1145. 

It is appropriate here to note that styrene is transformed by the black yeast Exophilia jeanselmei to phenylacetate by a pathway similar to that of the Xanthobacter sp. already noted. The initial monooxygenation was carried out by a cytochrome P450, and phenylacetate was further metabolized to 2-hydroxy- and 2,5-dihydroxyphenylacetate (Cox et al. 1996). 

Warhurst AM, CA Fewson (1994) Microbial metabolism and biotransformations of styrene. J Appl Bacterial 77 597-606. 

Several pathways are used for the aerobic degradation of aromatic compounds with an oxygenated C2 or C3 side chain. These include acetophenones and reduced compounds that may be oxidized to acetophenones, and compounds including tropic acid, styrene, and phenylethylamine that can be metabolized to phenylacetate, which has already been discussed. 

Duverger M, Lambotte M, Malvoisin E, et al. 1981a. Metabolic activation and mutagenicity of 4 vinylic monomers (vinyl chloride, styrene, acrylonitrile, butadiene). Toxicol Eur Res 3 131-140. 

Besides catalyzing styrene and benzaldehyde, CYP enzymes play an important role in the metabolism of endogenous compounds as well as in pharmacokinetics and toxicokinetics. Joseph [228] developed a biosensor with human CYP3A4 as a novel drugscreening tool. It was constructed by assembling enzyme films on Au electrodes by alternate adsorption of a layer of CYP3A4 on top of a layer of PDDA. The biosensor was applied to detect verapamil, midazolam, quinidine, and progesterone. 

Such stability is only relative, however, given the possibility of the acid-catalyzed 1,2-shift of a proton observed in some olefin epoxides of general structure 10.10 (Fig. 10.3) [12], Such a reaction occurs in the in vivo metabolism of styrene to phenylacetic acid the first metabolite formed is styrene oxide (10.10, R = Ph, Fig. 10.3, also 10.6), whose isomerization to phenyl-acetaldehyde (10.11, R = Ph, Fig. 10.3) and further dehydrogenation to phenylacetic acid has been demonstrated by deuterium-labeling studies. A com-... 

The data in Table 10.1 suggest that the reactivity of epoxide hydrolase toward alkene oxides is highly variable and appears to depend, among other things, on the size of the substrate (compare epoxybutane to epoxyoctane), steric features (compare epoxyoctane to cycloalkene oxides), and electronic factors (see the chlorinated epoxides). In fact, comprehensive structure-metabolism relationships have not been reported for substrates of EH, in contrast to some narrow relationships that are valid for closely related series of substrates. A group of arene oxides, along with two alkene oxides to be discussed below (epoxyoctane and styrene oxide), are compared as substrates of human liver EH in Table 10.2 [119]. Clearly, the two alkene oxides are among the better substrates for the human enzyme, as they are for the rat enzyme (Table 10.1). 

G. P. Carlson, Metabolism of Styrene Oxide to Styrene Glycol by Mouse Liver and Lung , J. Toxicol. Environ. Health 1998, 53, 19 - 27. 

T. Watabe, N. Ozawa, A. Hiratsuka, Studies on Metabolism and Toxicity of Styrene. VI. Regioselectivity in Glutathione 5-Conjugation and Hydrolysis of Racemic, R- and S-Phenyloxiranes in Rat Liver , Biochem. Pharmacol. 1983, 32, 111 - 785. 

It is interesting to note that the mandelic acid excreted in human mine after expostrre to ethylbenzene is predominantly the i -enantiomer, in contrast to the 1.2 1 mixture of R- and -mandelic acid excreted after styrene expostrre. Styrene and ethylberrzene share many common metabolic pathways, but there are evident differences in their stereoselectivity between the two compounds and this provides a means for selective monitoring of exposure to these solvents (Drummond et al., 1989 Kom etal, 1992). 

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